How Cannabis Helps with Bipolar Disorder
When we talk about the benefits of medical cannabis, we tend to focus on physical disorders: cancer, glaucoma, multiple sclerosis, etc. But medical cannabis patients also commonly use cannabis to help with psychiatric conditions such as depression and anxiety. And lately, more and more patients have been talking openly about using cannabis to treat bipolar disorder.
Bipolar disorder is characterized by swings between a manic state of elevated mood and increased energy and a depressed state of hopelessness and fatigue. The main treatments are psychotherapy and lithium, a mood stabilizer that can have undesirable side effects. Many patients looking for a better treatment have turned to cannabis.
Recently Gradi Jordan wrote a moving account of her struggles with bipolarity on Ladybud. She first used cannabis to treat her disorder at the age of ten, after in a fit of mania she had tried to stab her brother and take a door off its hinges.
“My mother told me I needed cannabis to calm down, or she would call the cops and have me arrested,” she explains. “This was my reality and the beginning of my appreciation and respect for cannabis.”
Jordan long used cannabis to treat her disorder, but she lives in Utah, where there is no medical cannabis, and underground cannabis is expensive. When she loses access to cannabis, her mental state deteriorates rapidly:
“When unable to afford or access cannabis, I tend to decompensate quickly and usually end up being forcibly admitted to lo\k down psychiatric facilities where numerous pharmaceuticals are pumped into my system, often times without my full consent or even knowledge. I eventually wind up having to undergo Electroconvulsive Therapy (ECT) as a last-ditch effort,” she says.
The ECT has taken a terrible toll on her mental health—she lost her memory, her concentration, and even her ability to read and write. She lost her job with the State of Utah and has been unable to find work.
Bipolar Disorder & Marijuana: How Cannabis Use Increases Cognitive Skills
Individuals with advanced neurocogitive skills compared to bipolar patients with no history of use, according to research published online in the journal Psychiatry Research.
Researchers from Zucker Hillside Hospital in Long Island, NY, along with colleagues at the Mount Sinai School of Medicine and the Albert Einstein College of Medicine in New York City compared the performance of 50 bipolar subjects with a history of marijuana use to 150 bipolar patients with no history of use with a series of standardized cognitive tests.
Patient groups were similar in regards to age, racial background, and highest education levels achieved. Bipolar patients with a history of marijuana use had similar age at onset as did study participants who had not smoked marijuana.
During the study, researchers discovered that participants with a history of smoking marijuana exhibited better neurocognitive performance than that of non-users, but there was no major difference on estimates of premorbid IQ.
“Results from our analysis suggest that subjects with bipolar disorder and history of (marijuana use) demonstrate significantly better neurocognitive performance, particularly on measures of attention, processing speed, and working memory.”
“These findings are consistent with a previous study that demonstrated that bipolar subjects with history of cannabis use had superior verbal fluency performance as compared to bipolar patients without a history of cannabis use. Similar results have also been found in schizophrenia in several studies,” said the authors.
“These data could be interpreted to suggest that cannabis use may have a beneficial effect on cognitive functioning in patients with severe psychiatric disorders. However, it is also possible that these findings may be due to the requirement for a certain level of cognitive function and related social skills in the acquisition of illicit drugs,” they said.
About the author and her other writings: Traci Pedersen
Source: Psychiatry Research
Perimenopause Part 2: How Cannabis Can Help with Hormone Induced Mood Swings
It is hard to imagine women in generations past having as many hormonal complications in the years leading up to menopause as today’s women do. Toxins in the air, food and water create xenoestrogens in the body. These aggressive foreign chemicals mask as natural estrogens and take their toll on women who are already experiencing the natural hormonal fluctuations of midlife to begin with.
In the last article, we presented a rather daunting list of the complications that can arise in women during perimenopause. Many of these things could be lessened, however, with the right formula of healthy lifestyle habits (such as getting plenty of rest and reducing stress), detoxing, healthy eating and targeted supplements.
And this is exactly where medical cannabis use can come in. Cannabis use can rebalance the vital Endo-Cannabinoid (ES) system during perimenopause, which in turn can assist in hormonal balancing.
Cannabis for Hormonal Mood Swings
The years directly before menopause are sometimes called the “window of vulnerability” for the development of a variety of psychological conditions, including depression, anxiety and sleep disturbances. Estrogen levels may fluctuate greatly during perimenopause while xenoestrogens continue to build up and estrogen methylation and metabolism issues arise. All this can lead to fibroid tumors, painful ovulation, breast cancer and severe mood swings.
Issues with estrogen also affects other hormones that are part of the endocrine system, such as testosterone and progesterone. All of these substances play a vital role when it comes to cognitive function and emotional balance. In addition to the specific physiological changes that middle-aged women go through, midlife can be a very stressful period in general, no matter what your gender. Aging parents, children leaving home, changes in work and career and the ending of relationships are just a few of the emotionally-charged situations that can come up during the “middle years.”
Given all these factors, is it no wonder that a study based out of Europe which questioned over 514 million people in over 30 countries found that depression in middle-aged women had double over the last 40 years?
In addition to cultivating self-awareness through counseling and modalities like EFT/Tapping(as well as the possible use of bioidentical hormones to increase progesterone levels naturally), low-level cannabis use can play a role in not only regulating a woman’s brain chemistry but also in possibly displacing harmful xenoestrogens.
The EC System and Estrogen
One reason cannabis benefits the brain is because of the neuro-protective role cannabinoids play in the body. In part because of the presence of the phytoestrogen apigenin, cannabis helps to mediate the growth of new brain cells and the connections that are formed between them. In a study using mice conducted by Hebrew University in Jerusalem, the cannabinoid 2-AG was believed to reduce the level of toxic molecules, decrease the amounts of inflammation-producing free radicals and increase the blood supply to the brain in traumatic brain injury.
Some research, such as that of a 2011 study conducted by the University of Newcastle in England, makes the direct correlation between EC System dysfunction and mood-related conditions as well as how cannabis can help.
“Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders,” the researchers said.
Interestingly, researchers at Newcastle noted that “abnormalities in cannabinoid-1 receptors (CNR1)” were found in psychiatric imbalances (when studied post-mortem). CNR1 is a gene that “codes” for cannabinoid-1 (CB1) receptors. Recalling from the last article, CB1 is also intricately connected to the functioning of the endocrine system since there are active cannabinoid receptors located within and near the hypothalamus. Research also indicates the presence of CB1 receptors within the gonads (ovaries and testes) of both men and women.
And this is where cannabis may be able to help perimenopausal women in another way. It was mentioned that apigenin, found in cannabis as well as beans and seeds like flax, is a “phytoestrogen.” That means that apigenin likes to bind with estrogen receptors in the body, often taking up the space that xenoestrogens would fill. In studies dating as far back as the 1980’s, there has been evidence that apigenin in cannabidiol has a high propensity for estrogen-receptor binding. One studyfrom 1983 stated that “estrogen receptor binding activity was observed in crude marijuana extract, marijuana smoke condensate and several known components of cannabis,” but not in straight extract.
Cannabis and Serotonin Levels
The body will respond to a perceived “threat” whether it is real or imagined. When it does, it creates a series of responses, the last of which is the adrenal release of cortisol, often called the “stress” hormone because it is activated during “fight or flight.” Several things happen when cortisol is let loose in body, the most significantly being that the body’s resources are diverted from digestion and immune function to the preparation of the body to either “run,” fight” or “go with the status quo.” Especially in conditions of chronic stress, such as depression or PTSD, levels of cortisol remain so high in the bloodstream that levels of serotonin and dopamine (those hormones associated with pleasure and relaxation) remain permanently low or nonexistent.
Cortisol levels tend to rise during the later stages of perimenopause and into menopause, although researchers have not been able to pinpoint exactly why. The consequences of this rise are noticeable, however: insomnia, weight gain, a compromised immune system and a greater chance for major anxiety/depression disorder. Some modalities and supplements, such as DHEA and massage, have demonstrated a clear ability to balance cortisol and serotonin. Early research also shows that very low doses of cannabis may also help regulate and stabilize serotonin levels, again through assisting in the proper functioning of endocannabinoids between neurological pathways. Anecdotal evidence from PTSD sufferers supports this hypothesis as well.
As is the case with every healing modality, the dosage and modality of cannabis use will vary for each woman. Cannabis smoke or vape (not extract) appear to be the best mode of administration for cannabis’ phytoestrogenic effect, while brain hormone-balancing effects seem to be effective in any form, but only with low doses. Caution should be taken when you are trying cannabis for mood-balancing for the first time in order to determine how it affects you. In addition, extra precautions need to be taken for women who have hypothyroidism. While there has been no evidence to suggest that cannabis use affects the thyroid with repeated use over time, other studies point to a slowing down of thyroid function with cannabis use in general.
The fundamental principle of natural medicine relies on the fact that the body is always seeking balance. Because cannabis aids in the healthy functioning of the endocannabinoid system (whose sole purpose is to create balance in the body!), it can be a great adjunct therapy for most perimenopausal women seeking relief. The best course of action is to consider cannabis within the larger framework of a healthy lifestyle overall. Learn all you can and then give a particular marijuana modality a try, being aware every step of the way of what feels right for you.
To learn more about medical cannabis, peri-menopause and other conditions, please join us for two days of education on May 21st and 22nd at Dominican University of California, located in the San Francisco bay
A Patients Guide for using Medical Marijuana for Anxiety, Sleep, Depression and Mood Disorders
One of the most well-known effects of cannabis is a feeling of overall well-being or happiness. Medical professionals and researchers refer to this effect as mood elevation, and know that it is caused by cannabinoids. Cannabinoids are chemical compounds in cannabis similar to those that the human body produces on its own when healthy. With certain conditions, such as anxiety, sleep, and mood disorders, the body may not produce these needed soothing agents. Medical marijuana can help replace these natural cannabinoids to relieve many of the symptoms common with depression, anxiety, sleep and mood disorders.
How Medical Marijuana Works for Anxiety, Sleep, Depression and Mood Disorders
It might seem strange that cannabis works across different anxiety, sleep, and mood disorders, since these conditions have many separate causes and symptoms that are not always related. One reason cannabis is effective is because it has 61 unique cannabinoids, each of which falls into one of eleven different groups that have different effects when used to treat conditions. This is why patients will see different strains of medical marijuana bred to have higher levels of specific cannabinoids. This specialization is based on years of deep scientific research.
- Therapies for major depression currently available have limited effectiveness, but research on cannabinoids shows that these compounds increase serotonin, an important mood controller, and even increases the generation of new brain cells (Endocannabinoids in the Treatment of Mood Disorders: Evidence from Animal Models, Rodriguez Bambico, F. et al.)
- Anxiety is a symptom of many psychiatric conditions, and recent research shows that the endocannabinoid system plays a role in modulating the feelings of fear that characterize anxiety. In particular, the CB1 receptor plays an important part, and can be activated to relieve feelings of anxiety with cannabinoids, either naturally produced or introduced into the body (such as with medical marijuana) (Modulation of Fear and Anxiety by the Endogenous Cannabinoid system, Chhatwal, J.P., and Ressler, K.J.)
- THC appears to be the primary cannabinoid contributing to feelings of sleepiness, while the cannabinoid CBD can cause feelings of wakefulness, suggesting that high-THC low-CBD strains of medical marijuana are best to overcome insomnia and sleeplessness (Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults, Nicholson, A.N., et al.)
- Adult medical cannabis users report more feelings of depression, possibly brought on by the conditions contributing to their use of medical cannabis, but also report relief from symptoms of depression and more positive moods through using medical cannabis (Decreased depression in marijuana users, Denson, T.F., and Earleywine, M.)
Since the cannabinoids that relieve symptoms of anxiety, sleep, and mood disorders are present in virtually any form of medical marijuana, patients can find relief from their symptoms in a variety of ways, including:
- Inhaled medical marijuana, whether through commonly used marijuana cigarettes or specialized devices such as pipes and vaporizers
- In recipes as a food item or as an addition to drinks; this method works best in edibles that have a higher oil content, since cannabinoids are oil soluble
Anxiety, sleep, and mood disorders can be very disruptive to daily life, but so can many of the traditional treatments available for these conditions. Those suffering from these upsetting symptoms might be able to supplement treatment for their conditions with medical cannabis, and should discuss this option with a qualified medical marijuana doctor.
United Patients Group is dedicated to making sure patients can have access to medicine that helps reduce their pain and symptoms, listing dispensaries and medical marijuana resources to ease that process. Feel free to contact us with any questions or to share your story of how medical marijuana has helped you.
Mood Disorders Information: Mood Disorders and Medical Marijuana Treatments
Most people feel sad or irritable from time to time. They may say they’re in a bad mood. A mood disorder is different. It affects a person’s everyday emotional state. Nearly one in ten people aged 18 and older have mood disorders. These include depression and bipolar disorder(also called manic depression).
Recent years have brought a wealth of new scientific understanding regarding how medical marijuana or cannabis can be beneficial for treating mood disorders.
Mood disorders can increase a person’s risk for heart disease, diabetes, and other diseases. Treatments include medication, psychotherapy, or a combination of both. With treatment, most people with mood disorders can lead productive lives.
Medications that relieve nausea and vomiting are called antiemetics, and are frequently prescribed for patients suffering from cancer, HIV/AIDs, Crohn’s disease, chronic anxiety, and other illnesses that cause nausea and vomiting. Antiemetics are needed because not only are the symptoms of nausea and vomiting painful and disruptive for the patient, but they can also cause dehydration and poor nutrition, leading to weight loss and other conditions that stall recovery. Through the actions of its unique compounds, known as cannabinoids, medical marijuana is widely recognized as an effective antiemetic.
How Medical Marijuana Works for Nausea and Vomiting (N/V)
In most episodes of nausea and vomiting, the digestive tract produces large amounts of gastric acids, either to promote these functions or as an irritant that causes these reactions. The body’s natural endocannabinoid system includes cannabinoid receptors in the digestive tract, and once these receptors are activated, the digestive tract reduces its production of these acids. These receptors are only activated when cannabinoids find and attach to the receptors, so ingesting or inhaling medical marijuana can reduce or stop the processes causing nausea and vomiting. Scientific studies show that this action makes medical marijuana an effective treatment:
- There is strong evidence that the cannabinoids naturally produced in the body play a role in suppressing nausea in normal circumstances, and intake of cannabinoids from medical marijuana during episodes of nausea can also effectively relieve symptoms (Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea, Parker et al.)
- Inhaled medical marijuana achieves superior results in reducing nausea and vomiting over synthetic alternatives (Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate, Chang, A.E. et al.)
- Vaporized, inhaled medical marijuana is a safe alternative to traditional smoked cannabis, and avoids many issues encountered with the ingestion of other medications, as swallowing medications during an episode of nausea or vomiting is uncomfortable and undesirable (Evaluation of a Vaporizing Device (Volcano) for the Pulmonary Administration of Tetrahydrocannabinol, Hazekamp, A. et al.)
- The body absorbs medical marijuana quickly because it is similar to the cannabinoids the body naturally produces. More cannabinoids are absorbed in inhaled form than in ingested form, since the body attempts to metabolize any ingested medication before absorption. This action also reduces the effectiveness of standard therapies, including synthetic cannabis (Physiochemical and pharmacological characterization of a delta(9)-THC aerosol generated by a metered dose inhaler, Wilson, D.M. et al.)
Since cannabis has fewer unpleasant side effects than other common treatment options for nausea and vomiting and provides relief from additional symptoms that often accompany chronic conditions, many patients rely on medical marijuana to ease nausea and vomiting. Methods through which this relief can be obtained include:
- Traditionally inhaled cannabis, such as through a marijuana cigarette or other smoked delivery device
- Vaporized cannabis, which is heated using special equipment so that the vapors can be inhaled
- Cannabis specially prepared in edibles or tinctures
The nausea and vomiting caused by chronic conditions can be extremely uncomfortable. For many conditions, proper nutrition and a steady body weight are essential for successful disease management, which can be a problem when stomach discomfort prevents patients from enjoying their food.
United Patients Group is dedicated to making sure patients can access medical marijuana, not only to relieve nausea and vomiting and increase appetite, but also as an effective treatment for other medical conditions. Please visit our New Patients Room for more information how cannabis helps relieve pain and symptoms of chronic illnesses.
Nausea Information: Nausea and Medical Marijuana Treatments
Nausea is an uneasy or unsettled feeling in the stomach together with an urge to vomit. Nausea and vomiting, or throwing up, are not diseases. They can be symptoms of many different conditions. These include morning sickness during pregnancy, infections, migraine headaches, motion sickness, food poisoning, cancer chemotherapy or other medicines.
Recent years have brought a wealth of new scientific understanding regarding how medical marijuana or cannabis can be beneficial for treating Nausea.
For vomiting in children and adults, avoid solid foods until vomiting has stopped for at least six hours. Then work back to a normal diet. Drink small amounts of clear liquids to avoid dehydration.
Nausea and vomiting are common. Usually, they are not serious. You should see a doctor immediately if you suspect poisoning or if you have
- Vomited for longer than 24 hours
- Blood in the vomit
- Severe abdominal pain
- Headache and stiff neck
- Signs of dehydration, such as dry mouth, infrequent urination or dark urine
Intractable Vomiting and Marijuana Information: Treat Nausea With Cannabis
Intractable vomiting is repeated vomiting that resists medical treatment. People can develop this symptom for a number of reasons and treatment is focused on providing supportive care to keep the patient as comfortable as possible until the cause can be resolved. There are some risks associated with intractable vomiting, including dehydration and the possibility of a hiatal hernia, where part of the stomach slips through the diaphragm and into the upper chest.
In people with intractable vomiting, repeated bouts of vomiting are experienced and may be accompanied with loss of appetite, headaches, nausea while not vomiting, and general discomfort. The vomiting does not resolve and antiemetic drugs may not suppress it. Patients can also feel weak or dizzy as a result of the strain associated with vomiting, and may develop complications like sore throats and dental damage.
Regulation of nausea and vomiting by cannabinoids
Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ9-THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.
This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7
A major advance in the control of acute emesis in chemotherapy treatment was the finding that blockade of one subtype of the 5-hydroxytryptamine (5-HT) receptor, the 5-HT3 receptor, could suppress the acute emetic response (retching and vomiting) induced by cisplatin in the ferret and the shrew (Costall et al., 1986; Miner and Sanger, 1986; Ueno et al., 1987; Matsuki et al., 1988; Torii et al., 1991). In clinical trials with humans, treatment with 5-HT3 antagonists often combined with the corticosteroid dexamethasone during the first chemotherapy treatment reduced the incidence of acute vomiting by approximately 70% (e.g. Bartlett and Koczwara, 2002; Aapro et al., 2003; Ballatori and Roila, 2003; Hickok et al., 2003; Andrews and Horn, 2006). However, the 5-HT3 antagonists are less effective at suppressing acute nausea than they are at suppressing acute vomiting (Morrow and Dobkin, 1988; Bartlett and Koczwara, 2002; Hickok et al., 2003) and they are ineffective at reducing instances of delayed (24 h later) nausea and vomiting (Morrow and Dobkin, 1988; Grelot et al., 1995; Rudd et al., 1996; Rudd and Naylor, 1996; Tsukada et al., 2001; Hesketh et al., 2003) and anticipatory (conditioned) nausea and vomiting (Nesse et al., 1980; Morrow and Dobkin, 1988; Hickok et al., 2003).
More recently, NK1 receptor antagonists (e.g. aprepitant) have been developed that not only decrease acute vomiting, but also decrease delayed vomiting induced by cisplatin-based chemotherapy (Van Belle et al., 2002); however, these compounds alone and in combination with 5-HT3 antagonist/dexamethasone treatment are also much less effective in reducing nausea (e.g. Hickok et al., 2003; Andrews and Horn, 2006; Slatkin, 2007), which is the symptom reported to be the most distressing to patients undergoing treatment with 5-HT3 antagonists (deBoer-Dennert et al., 1997). Considerable evidence suggests that another system that may be an effective target for treatment of chemotherapy-induced nausea, delayed nausea/vomiting and anticipatory nausea (AN)/vomiting is the endocannabinoid system (e.g. for review, Parker and Limebeer, 2008).
Anti-emetic effects of cannabinoids in human clinical trials
The cannabis plant has been used for several centuries for a number of therapeutic applications (Mechoulam, 2005), including the attenuation of nausea and vomiting. Ineffective treatment of chemotherapy-induced nausea and vomiting prompted oncologists to investigate the anti-emetic properties of cannabinoids in the late 1970s and early 1980s, before the discovery of the 5-HT3 antagonists. The first cannabinoid agonist, nabilone (Cesamet), which is a synthetic analogue of Δ9-THC was specifically licensed for the suppression of nausea and vomiting produced by chemotherapy. Furthermore, synthetic Δ9-THC, dronabinol, entered the clinic as Marinol in 1985 as an anti-emetic and in 1992 as an appetite stimulant (Pertwee, 2009). In these early studies, several clinical trials compared the effectiveness of Δ9-THC with placebo or other anti-emetic drugs. Comparisons of oral Δ9-THC with existing anti-emetic agents generally indicated that Δ9-THC was at least as effective as the dopamine antagonists, such as prochlorperazine (Carey et al., 1983; Ungerleider et al., 1984; Crawford and Buckman, 1986; Cunningham et al., 1988; Tramer et al., 2001; Layeeque et al., 2006).
There is some evidence that cannabis-based medicines may be effective in treating the more difficult to control symptoms of nausea and delayed nausea and vomiting in children. Abrahamov et al. (1995)evaluated the anti-emetic effectiveness of Δ8-THC, a close but less psychoactive relative of Δ9-THC, in children receiving chemotherapy treatment. Two hours before the start of each cancer treatment and every six hours thereafter for 24 h, the children were given Δ8-THC as oil drops on the tongue or in a bite of food. After a total of 480 treatments, the only side effects reported were slight irritability in two of the youngest children (3.5 and 4 years old); both acute and delayed nausea and vomiting were controlled.
Surprisingly, only one reported clinical trial (Meiri et al., 2007) has compared the anti-emetic/anti-nausea effects of cannabinoids with those of the more recently developed 5-HT3 antagonists and none has compared cannabinoids with the NK1 antagonist, aprepitant. Meiri et al. (2007) compared the efficacy and tolerability of dronabinol, ondansetron or the combination for delayed chemotherapy-induced nausea and vomiting in a 5 day, double-blind, placebo-controlled study. Patients that were receiving moderately to highly emetogenic chemotherapy were all given both dexamethasone and ondansetron, with half also receiving placebo and half receiving dronabinol prechemotherapy on Day 1. On Days 2–5, they received placebo, dronabinol, ondansetron or both dronabinol and ondansetron. The results of the study indicated that the efficacy of dronabinol alone was comparable with ondansetron in the treatment of delayed nausea and vomiting, for the total response of no vomiting/retching and nausea less than 5 mm on a visual analogue scale. Rates of absence of nausea were 71% with dronabinol, 64% with ondansetron and 15% with placebo; also the dronabinol group reported the lowest nausea intensity on a visual analogue scale (10.1 mm vs. 24 mm with ondansetron and 48.4 mm with placebo). However, the combined treatment (ondansetron and dronabinol) was no more effective than either agent alone. The dose of dronabinol used in the present study was at least 50% less than in previous studies resulting in a low incidence of CNS-related adverse effects, which did not differ from the incidence in the ondansetron-treated group. Although the study was not explicitly designed to evaluate the effects of combined therapy on acute nausea and vomiting, the combined active treatment group reported less nausea and vomiting on the chemotherapy treatment day than the placebo group.
All reported clinical trials for the effectiveness of cannabinoid compounds on chemotherapy-induced nausea and vomiting have involved oral use of cannabinoids, which may be less effective than sublingual or inhaled cannabinoids, given the need to titrate the dose (Hall et al., 2005). Recently, in 2005, Sativex (GW Pharmaceuticals), a combination of Δ9-THC and the non-psychoactive plant cannabinoid, cannabidiol (CBD), was made available as a sublingual spray for the relief of neuropathic pain in patients with multiple sclerosis and in cancer patients with advanced pain (Johnson et al., 2010). However, to the best of our knowledge, the effectiveness of this compound in reducing nausea and vomiting has not been evaluated. Many patients have a strong preference for smoked marijuana over the synthetic cannabinoids delivered orally (Tramer et al., 2001). Several reasons for this have been suggested: (i) advantages of self-titration with the smoked marijuana; (ii) difficulty in swallowing the pills while experiencing emesis; (iii) faster speed of onset for the inhaled or injected Δ9-THC than oral delivery; (iv) a combination of the action of other cannabinoids with THC that are found in marijuana. Although many marijuana users have claimed that smoked marijuana is a more effective anti-emetic than oral THC, no controlled studies have yet been published that evaluate this possibility.
Effects of cannabinoids on vomiting in animal models
To evaluate the anti-emetic potential of drug therapies, animal models have been developed. Since rats and mice do not vomit in response to a toxin challenge, it is necessary to use other animal models of vomiting. There is considerable evidence that cannabinoids attenuate vomiting in emetic species (reviewed in Parker et al., 2005; Parker and Limebeer, 2008). Cannabinoid agonists have been shown to reduce vomiting in cats (McCarthy and Borison, 1981), pigeons (Feigenbaum et al., 1989; Ferrari et al., 1999), ferrets (Simoneau et al., 2001; Van Sickle et al., 2001; 2003; 2005;), least shrews, Cryptotis parva (Darmani, 2001a,b,c; 2002; Darmani and Johnson, 2004; Darmani et al., 2005; Ray et al., 2009; Wang et al., 2009) and the house musk shrew, Suncus murinus (Kwiatkowska et al., 2004; Parker et al., 2004). As well as attenuating acute vomiting produced by cisplatin, Δ9-THC also attenuates delayed vomiting in the least shrew (Ray et al., 2009).
Anti-emetic effect of cannabinoids: mechanisms of action
The mechanism of action of the suppression of nausea and vomiting produced by cannabinoids has recently been explored with the discovery of the endocannabinoid system and the development of animal models of nausea and vomiting. Recent reviews on the gastrointestinal effects of cannabinoids have concluded that cannabinoid agonists act mainly via peripheral CB1 receptors to decrease intestinal motility (Pertwee, 2001), but may act centrally to attenuate emesis (Van Sickle et al., 2001). The dorsal vagal complex (DVC) is involved in the vomiting reactions induced by either vagal gastrointestinal activation or several humoral cytotoxic agents. The DVC is considered to be the starting point of a final common pathway for the induction of emesis in vomiting species. The DVC consists of the area postrema (AP), nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMNX) in the brainstem of rats, ferrets and the least shrew. CB1 receptors, as well as the catabolic enzyme of anandamide, fatty acid amide hydroxyslase (FAAH), have been found in areas of the brain involved in emesis, including the DMNX (Van Sickle et al., 2001).
CB1 receptors in the NTS are activated by Δ9-THC and this activation is blocked by the selective CB1antagonist/inverse agonists, SR-141716, known as rimonabant (Darmani et al., 2005) and AM251 (Van Sickle et al., 2003). In fact, at higher doses than those required to reverse the anti-emetic effects of Δ9-THC, rimonabant produces emesis on its own in the least shrew (Darmani, 2001c) and AM-251 potentiates cisplatin-induced emesis in the ferret (Van Sickle et al., 2001). Molecular markers of activation also implicate the role of central CB1 receptors in the anti-emetic effects of Δ9-THC. Cisplatin pretreatment results in c-fos expression in the DMNX, specific subnuclei of the NTS and AP, which is significantly reduced by pretreatment with Δ9-THC (Van Sickle et al., 2001; 2003;). Endogenous cannabinoid ligands, such as anandamide and 2-arachidonyol glycerol (2-AG), as well as synthetic cannabinoids, such as WIN 55,212–2, also act on these receptors (Simoneau et al., 2001). However, Darmani and Johnson (2004)provide evidence that both central and peripheral mechanisms contribute to the actions of Δ9-THC against emesis produced by 5-hydroxytryptophan (5-HTP), the precursor to 5-HT in the least shrew. At lower doses, Δ9-THC acts centrally as an anti-emetic, but at higher doses (10 mg·kg−1) it acts peripherally.
Although anandamide has been reported to have anti-emetic properties in the ferret (Van Sickle et al., 2001) and the least shrew (Darmani, 2002), the role of 2-AG in the regulation of nausea and vomiting is less clear. Darmani (2002) found that 2-AG (2.5–10 mg·kg−1, i.p.) produces emesis in the least shrew, most likely via its downstream metabolites, because its emetic activity can be blocked by both rimonabant and the the COX inhibitor, indomethacin. An evaluation of changes in endocannabinoid levels elicited by cisplatin revealed that cisplatin increased levels of 2-AG in the brainstem, but decreased intestinal levels of both 2-AG and anandamide (Darmani et al., 2005). Darmani et al. (2005) suggested that the central elevation of 2-AG may contribute to the emetic potential of cisplatin (in addition to mobilizing the release of known emetic stimuli such as 5-HT, dopamine and substance P). On the other hand, Van Sickle et al. (2005) reported that 2-AG is anti-emetic in ferrets treated with the emetogenic agent morphine-6-glucuronide (M6G). CB2 receptors in the brainstem may play a role in the regulation of emesis by 2-AG, at least when CB1 receptors are co-stimulated. The anti-emetic effects of 2-AG (0.5–2.0 mg·kg−1) in ferrets were reversed by both CB1 (AM251) and CB2 (AM630) antagonists, but the anti-emetic effects of anandamide were only reversed by AM251. Therefore, 2-AG, unlike anandamide, may selectively activate these brainstem CB2 receptors (Van Sickle et al., 2005). Finally, consistent with the anti-emetic effects of 2-AG in the ferret, the monoacylglycerol-lipase (MAGL) inhbitior, JZL-184 (Long et al., 2009a,b;), which elevates endogenous 2-AG, dose-dependently suppresses vomiting in the S. murinus (Sticht et al., 2010). Furthermore, in vitro data revealed that JZL 184 inhibited MAGL expression in shrew tissue.
The FAAH inhibitor, URB597, alone and in combination with exogenously administered anandamide has been shown to interfere with vomiting produced by M6G in the ferret (Van Sickle et al., 2005; Sharkey et al., 2007) and with nicotine and cisplatin in S. murinus (Parker et al., 2009a). Although inhibition of FAAH elevates multiple endocannabinoid-like molecules that show activity at multiple target receptors, the anti-emetic effects of URB 597 were reversed by pretreatment with rimonabant, indicating a CB1 mechanism of action. There may be a species difference in this effect, because URB597 (5 or 10 mg·kg−1) administered to the least shrew did not modify toxin-induced vomiting (Darmani et al., 2005); yet in this latter study URB597 was administered only 10 min prior to cisplatin at a time that may not have produced sufficient inhibition of FAAH prior to the onset of the toxin effect (Fegley et al., 2005). In experiments with the S. murinus, a much lower dose (0.9 mg·kg−1) administered 2 h prior to the toxin challenge suppressed vomiting.
A relative of the cannabinoid system, vanilloid TRPV1 receptors have recently been shown to regulate emesis in the ferret (Sharkey et al., 2007). The TRPV1 receptor is targeted by capsaicin (the burning component of chili peppers) as well as resiniferatoxin, which can produce pro-emetic and anti-emetic effects at similar doses in S. murinus (Andrews et al., 2000), but produces anti-emetic effects in ferrets (Andrews and Bhandari, 1993; Andrews et al., 2000; Yamakuni et al., 2002). Recent evidence indicates that anandamide and the endovanniloid, N-arachidonoyl-dopamine (NADA), are endogenous agonists for both CB1 and TRPV1 receptors (Di Marzo and Fontana, 1995; van der Stelt and DiMarzo, 2004). Extensive colocalization of CB1 and TRPV1 receptors have been demonstrated (Cristino et al., 2006). Both endogenous (anandamide, NADA) and synthetic (arvanil or O-1861) ‘hybrid’ agonists of CB1 and TRPV1 receptors have been shown to exert more potent pharmacological effects in vivo (Di Marzo et al., 2001) than ‘pure’ agonists of each receptor type, particularly when acting on cells co-expressing the two receptor types (Hermann et al., 2003). Sharkey et al. (2007) found that anandamide, NADA and arvanil were all anti-emetic in the ferret; these effects were attenuated by the CB1 receptor inverse agonist AM251 and the TRPV1 antagonists iodoresiniferatoxin and AMG9810. TRPV1 receptors were localized in the ferret NTS and were co-localized with CB1 in the mouse brainstem.
Recent findings indicate that the cannabinoid system interacts with the 5-hydroxytryptaminergic system in the control of emesis (e.g. Kimura et al., 1998). The DVC not only contains CB1 receptors, but is also densely populated with 5-HT3 receptors (Himmi et al., 1996; 1998;), potentially a site of anti-emetic effects of 5-HT3 antagonists. Cannabinoid receptors are co-expressed with 5-HT3 receptors in some neurones in the CNS (Hermann et al., 2002). The first evidence of an interaction between cannabinoids and 5-HT3 receptors was revealed by the finding that anandamide, WIN55 212 and CP55940 inhibit 5-HT3receptor-mediated inward currents with IC50 values in the nanomolar concentration range in rat nodose ganglion cells (Fan, 1995). Subsequently, Δ9-THC, anandamide and several synthetic cannabinoids were shown to directly inhibit currents through human 5-HT3A receptors (Barann et al., 2002). Since WIN 55,212–2 did not displace a 5-HT3 antagonist ([3H]-GR65630) from the ligand binding site, the results suggest that cannabinoids inhibit 5-HT3A receptors noncompetitively by binding to an allosteric modulatory site of the receptor (Barann et al., 2002). Indeed, anandamide produced analgesia in CB1/CB2knockout mice that was prevented by pretreatment with the 5-HT3 antagonist, ondansetron (Racz et al., 2008). In the regulation of vomiting, low doses of Δ9-THC and ondansetron that were ineffective alone completely suppressed cisplatin-induced vomiting in the S. murinus (Kwiatkowska et al., 2004) and the combination of low doses of tropisetron and Δ9-THC were more efficacious in reducing emesis frequency in the least shrew than when given individually (Wang et al., 2009). Additionally, cannabinoids have been shown to reduce the ability of 5-HT3 agonists to produce emesis (Darmani and Johnson, 2004) and this effect was prevented by pretreatment with rimonabant. Cannabinoids may act at CB1 presynaptic receptors to inhibit the release of newly synthesized 5-HT (Schlicker and Kathmann, 2001; Howlett et al., 2002; Darmani and Johnson, 2004). Indeed, Darmani et al. (2003) reported that rimonabant (which produces vomiting in the least shrew) increases brain 5-HT levels and turnover at doses that induce vomiting in the shrew.
CBD: a special case
Another major cannabinoid found in marijuana is CBD. Unlike Δ9-THC, CBD does not produce intoxicating effects and has a low affinity for the CB1 and CB2 receptors (Mechoulam et al., 2002). At a low dose, CBD (5 mg·kg−1, i.p.) inhibits cisplatin-induced (Kwiatkowska et al., 2004) and LiCl-induced (Parker et al., 2004) vomiting and anticipatory retching (Parker et al., 2006) in S. murinus. As has been reported by others (e.g. Pertwee, 2004), the effects of CBD are biphasic with high doses (20–40 mg·kg−1, i.p.) potentiating toxin-induced vomiting in the S. murinus (Parker et al., 2004; Kwiatkowska et al., 2004), but a dose as high as 20 mg·kg−1 of CBD had no effect on 2-AG-induced emesis in the least shrew (Darmani, 2002). A wide range of doses was not effective in reducing motion-induced emesis in the S. murinus (Cluny et al., 2008), which may reflect a different mechanism of action of motion and toxin-induced vomiting (Cluny et al., 2008).
The anti-emetic effect of CBD does not appear to be mediated by its action at CB1 receptors, because it is not reversed by the CB1 antagonist, rimonabant (Kwiatkowska et al., 2004; Parker et al., 2004). Recent evidence indicates that CBD may act as an indirect agonist on the 5-HT1A autoreceptors, to reduce the availability of 5-HT (Russo et al., 2005; E.M. Rock et al., unpubl. obs.). Known 5-HT1A autoreceptor agonists such as 8-OH-DPAT, buspirone, and LY228729, have been found to suppress vomiting in emetic species such as pigeons (Wolff and Leander, 1994; 1995; 1997;), shrews (Okada et al., 1994; Andrews et al., 1996; Javid and Naylor, 2006), cats (Lucot and Crampton, 1989; Lucot, 1990) and dogs (Gupta and Sharma, 2002). Indeed, Russo et al. (2005) reported that CBD displaces the agonist [3H]-8-OH-DPAT from a cloned human 5HT1A receptor in a concentration-dependent manner. Furthermore, CBD was shown to act as an agonist at the 5HT1A receptor, because, like 5HT, it increased GTP binding to the receptor coupled G protein, Gi, characteristic of a receptor agonist. Finally, the agonist CBD was shown to reduce cAMP production, characteristic of Gi activation.
Recently, our laboratory has investigated the mechanism of action for the anti-emetic effects of CBD. Consistent with previous results, CBD (5 mg·kg−1, s.c.) was shown to be effective in suppressing vomiting in the S. murinus induced by either nicotine, LiCl or cisplatin (20 mg·kg−1, but not 40 mg·kg−1). Interestingly, this CBD-induced suppression of vomiting was reversed by systemic pretreatment with the 5-HT1A antagonist WAY100135 (E.M. Rock et al., unpubl. obs.), suggesting that the anti-emetic effect of CBD may be mediated by activation of somatodendritic autoreceptors. This activation of the 5-HT1Areceptors results in a reduction of the rate of firing of 5-HT neurones, ultimately reducing the release of forebrain 5-HT (Blier and de Montigny, 1987). It is this reduction in 5-HT release that is probably mediating CBD’s anti-emetic effects. In addition, a recent finding suggests that CBD may also act as an allosteric modulator of the 5-HT3 receptor (Yang et al., 2010); CBD reversibly inhibited 5-HT-evoked currents in 5-HT3A receptors expressed in Xenopus laevis oocytes in a concentration-dependent manner (1 µM), but did not alter the specific binding of a 5-HT3A antagonist. These findings suggest that allosteric inhibition of 5-HT3 receptors by CBD may also contribute to its role in the modulation of emesis.
Effects of cannabinoids on nausea in animal models
Nausea is more resistant to effective treatment with new anti-emetic agents than is vomiting (e.g. Andrews and Horn, 2006) and therefore remains a significant problem in chemotherapy treatment and as a side effect from other pharmacological therapies, such as anti-depressants. Even when the cisplatin-induced emetic response is blocked in the ferret by administration of a 5-HT3 receptor antagonist, c-fos activation still occurs in the AP, suggesting that an action here may be responsible for some of the other effects of cytotoxic drugs, such as nausea or reduced food intake (Reynolds et al., 1991). In rats, the gastric afferents respond in the same manner to physical and chemical (intragastric copper sulphate and cisplatin) stimulation that precedes vomiting in ferrets, presumably resulting in nausea that precedes vomiting (Hillsley and Grundy, 1998; Billig et al., 2001). Furthermore, 5-HT3 antagonists that block vomiting in ferrets also disrupt this preceding neural afferent reaction in rats. That is, in the rat the detection mechanism of nausea is present, but the vomiting response is absent. Nauseogenic doses of cholecystokinin and LiCl induce specific patterns of brainstem and forebrain c-fos expression in ferrets that are similar to c-fos expression patterns in rats (Reynolds et al., 1991; Billig et al., 2001). In a classic review paper, Borrison and Wang (1953) suggest that the rats’ inability to vomit can be explained as a species-adaptive neurological deficit and that, in response to emetic stimuli, the rat displays autonomic and behavioural signs corresponding to the presence of nausea, called the prodromata (salivation, papillary dilation, tachypnoea and tachycardia).
Conditioned taste avoidance: a nonselective measure of nausea in rats
The typical measure used in the literature to evaluate the nauseating potential of a drug is conditioned taste avoidance. However, taste avoidance is not only produced by nauseating doses of drugs, it is also produced by drugs that animals choose to self-administer or that establish a preference for a distinctive location (e.g. Berger, 1972; Wise et al., 1976; Reicher and Holman, 1977). In fact, when a taste is presented prior to a drug self-administration session, the strength of subsequent avoidance of the taste is a direct function of intake of the drug during the self-administration session (Wise et al., 1976; Grigson and Twining, 2002). This paradoxical phenomenon was initially interpreted as another instance of taste aversion learning. Because Garcia et al. (1974) had developed a model to account for taste aversion produced by emetic agents, it was reasonable for early investigators to assume that rewarding doses of drugs also produce taste avoidance because they produce a side effect of nausea that becomes selectively associated with a flavour (Reicher and Holman, 1977). However, in an animal capable of vomiting, the S. murinus, rewarding drugs do not produce a conditioned taste avoidance, in fact they produce a conditioned taste preference and a conditioned place preference (Parker et al., 2002a). Since rats are incapable of vomiting, it is likely that conditioned taste avoidance produced by rewarding drugs in this species is based upon a learned fear of anything that changes their hedonic state (e.g. Gamzu, 1977) when that change is paired with food previously eaten.
Another approach to understanding the role that nausea plays in the establishment of taste avoidance in rats is to evaluate the potential of anti-nausea treatments to interfere with avoidance of a flavour paired with an emetic treatment. Early work suggested that anti-nausea agents interfered with the expression of previously established taste avoidance produced by LiCl (Coil et al., 1978); however, more recent findings suggest that similar anti-nausea treatments (Goudie et al., 1982; Rabin and Hunt, 1983; Parker and McLeod, 1991) and different anti-nausea treatments (Gadusek and Kalat, 1975; Limebeer and Parker, 2000; 2003; Parker et al., 2002b; 2003😉 failed to interfere with the expression of LiCl-induced taste avoidance. Furthermore, there is considerable evidence that anti-nausea treatments either do not interfere with the establishment of conditioned taste avoidance learning (Rabin and Hunt, 1983; Rudd et al., 1998; Limebeer and Parker, 2000; Parker et al., 2002b) or at least only interfere with the establishment of very weak LiCl-induced taste avoidance (Wegener et al., 1997; Gorzalka et al., 2003). Two prominent anti-nausea treatments include drugs that reduce 5-HT availability and drugs that elevate the activity of the endocannabinoid system in rats (see Parker et al., 2005; 2009b; Parker and Limebeer, 2008). These treatments interfere with the establishment and/or the expression of conditioned disgust reactions, but not conditioned taste avoidance (for review, see Parker, 2003; Parker et al., 2009b).
Conditioned gaping: a selective measure of nausea in rats
Over the past number of years, our laboratory has provided considerable evidence that conditioned nausea in rats may be displayed as conditioned disgust reactions (Parker, 1982; 1995; 1998; 2003; Limebeer and Parker, 2000; 2003; Limebeer et al., 2004; Parker et al., 2008; 2009b😉 using the taste reactivity (TR) test (Grill and Norgren, 1978). Rats display a distinctive pattern of disgust reactions (including gaping, chin rubbing and paw treading) when they are intraorally infused with a bitter tasting quinine solution. Rats also display this disgust pattern when infused with a sweet tasting solution (that normally elicits hedonic reactions of tongue protrusions) that has previously been paired with a drug that produces vomiting (such as LiCl or cyclophosphamide) in species capable of vomiting. Only drugs with emetic properties produce this conditioned disgust reaction when paired with a taste.
The most reliable conditioned disgust reaction in the rat is that of gaping (Breslin et al., 1992; Parker, 2003). If conditioned gaping reflects nausea in rats, then anti-nausea drugs should interfere with this reaction. Limebeer and Parker (2000) demonstrated that when administered prior to a saccharin-LiCl pairing, the 5-HT3 antagonist, ondansetron, prevented the establishment of conditioned gaping in rats, presumably by interfering with LiCl-induced nausea. Since ondansetron did not modify unconditioned gaping elicited by bitter quinine solution, the effect was specific to nausea-induced gaping. Subsequently, Limebeer and Parker (2003) demonstrated a very similar pattern following pretreatment with the 5-HT1Aautoreceptor antagonist, 8-OH-DPAT, that also reduces 5-HT availability and serves as an anti-emetic agent in animal models. Most recently, Limebeer et al. (2004) reported that lesions of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) that reduced forebrain 5-HT availability interfered with the establishment of LiCl-induced conditioned gaping consistent with reports that reduced 5-HT availability interferes with nausea. Since rats are incapable of vomiting, we have argued that the gape represents an ‘incipient vomiting response’. The orofacial characteristics of the rat gape are very similar to those of the shrew retch just before it vomits (Parker, 2003). Indeed, Travers and Norgren (1986) suggest that the muscular movements involved in the gaping response mimic those seen in species capable of vomiting.
Effects of cannabinoids on nausea in rats
Using the conditioned gaping response as a measure of nausea in rats, we have demonstrated that a low dose (0.5 mg·kg−1, i.p.) of Δ9-THC interferes with the establishment and the expression of cyclophosphamide-induced conditioned gaping (Limebeer and Parker, 1999). The potent agonist, HU-210 (0.001–0.01 mg·kg−1), also suppressed LiCl-induced conditioned gaping (Parker and Mechoulam, 2003; Parker et al., 2003) and this suppression was reversed by the CB1 antagonist/inverse agonist, rimonabant, suggesting that the effect of HU-210 was mediated by its action at CB1 receptors. When administered 30 min prior to the conditioning trial, rimonabant did not produce conditioned gaping on its own, but it did potentiate the ability of LiCl to produce conditioned gaping. This same pattern has been reported in the emesis literature (Van Sickle et al., 2001; Chambers et al., 2007). Van Sickle et al. (2001) reported that although the CB1 antagonist/inverse agonist AM251 did not produce vomiting on its own, it potentiated the ability of an emetic stimulus to produce vomiting in the ferret.
More compelling evidence that the endocannabinoid system may serve as a regulator of nausea is the recent finding that prolonging the duration of action of anandamide by pretreatment with URB597, a drug that inhibits the enzyme FAAH, also disrupts the establishment of LiCl-induced conditioned gaping reactions in rats (Cross-Mellor et al., 2007). Rats pretreated with URB597 (0.3 mg·kg−1, i.p.) 2 h prior to a saccharin-LiCl pairing displayed suppressed conditioned gaping reactions in a subsequent drug free test. Rats given the combination of URB597 (0.3 mg·kg−1, i.p.) and anandamide (5 mg·kg−1, i.p.) displayed even greater suppression of conditioned gaping reactions. Although inhibition of FAAH produces an elevation of a variety of fatty acids that act at different receptors, the effect of URB597 on conditioned nausea was reversed by AM251, indicating that it was mediated by CB1 receptors.
At doses (greater than 4 mg·kg−1) that effectively suppress feeding in rats, the CB1 antagonist/inverse agonist AM251 produces conditioned gaping reactions when explicitly paired with saccharin solution (McLaughlin et al., 2005) reflective of nausea. This finding suggests that the appetite suppressant effect of the newly marketed CB1 antagonist/inverse agonist, rimonabant, may be partially mediated by the side effect of nausea, which is the most commonly reported side effect in human randomized control trials (Pi-Sunyer et al., 2006). On the other hand, the silent CB1 antagonists, AM4113 and AM6527, which do not have inverse agonist properties, do not produce conditioned gaping (Sink et al., 2007; Limebeer et al., 2010). In addition, the peripherally restricted silent CB1 antagonist, AM6545, which also suppresses feeding at equivalent doses of AM251 (Cluny et al., 2010; Randall et al., 2010; Tam et al., 2010), does not produce the side effect of nausea (Cluny et al., 2010). Finally, neither the silent antagonist, AM6527 (which crosses the blood–brain barrier) nor AM6545 (with limited CNS penetration), potentiate LiCl-induced nausea, an effect evident with low doses (2.5 mg·kg−1) of systemic administration of AM-251 (Limebeer et al., 2010). AM251-induced conditioned nausea is thus mediated by inverse agonism of the CB1 receptor. This effect may be mediated peripherally, because intracranial administration of AM251 at doses up to 1/10 the peripheral dose into the lateral ventricle or the 4th ventricle did not potentiate LiCl-induced nausea that is evident with systemic administration of this inverse agonist of the CB1 receptor.
CBD reduces nausea by a non-cannabinoid mechanism of action
In addition, the non-intoxicating compound found in marihuana smoke, CBD (5 mg·kg−1, i.p.) as well as its synthetic dimethylheptyl homologue (5 mg·kg−1, i.p.), suppresses the establishment and the expression of LiCl-induced conditioned gaping (Parker et al., 2002b; Parker and Mechoulam, 2003). Recent research (Rock et al., 2010) demonstrates that the anti-nausea effects of CBD (5 mg·kg−1, s.c.) are suppressed by systemic pretreatment with the 5-HT1A receptor antagonist WAY100135 (10 mg·kg−1, i.p.). In addition, the more selective 5-HT1A receptor antagonist, WAY100635, administered systemically (0.1 mg·kg−1, i.p.) or intracranially (21 ng in 0.5 µL) into the DRN, a site of somatodendritic 5-HT1A autoreceptors, interferes with the CBD-induced suppression of LiCl-induced conditioned gaping in rats. This effect was selective to receptors located in the DRN, as those rats with misplaced cannulae that received CBD outside of the DRN did not show a similar effect. In addition, when administered directly into the DRN, CBD (10 µg·µL−1) suppressed LiCl-induced gaping. These results suggest that CBD produces its anti-emetic/anti-nausea effects by activation of somatodentritic autoreceptors located in the DRN, reducing the release of forebrain 5-HT. Since depletion of forebrain 5-HT by 5,7-DHT lesions of the DRN and MRN also prevented the establishment of LiCl-induced conditioned gaping (Limebeer et al., 2004), nausea appears to be mediated by 5-HT action in forebrain regions. Research aimed at determining the forebrain regions (e.g. insular cortex) responsible for the sensation of nausea are currently being conducted in our laboratory (Tuerke et al., 2010).
Cannabinoids and AN in rats and shrews
AN often develops over the course of repeated chemotherapy sessions (Nesse et al., 1980; Morrow and Dobkin, 1988; Reynolds et al., 1991; Stockhorst et al., 1993; Aapro et al., 1994; Ballatori and Roila, 2003; Hickok et al., 2003). For instance, Nesse et al. (1980) described the case of a patient who had severe nausea and vomiting during repeated chemotherapy treatments. After his third treatment, the patient became nauseated as soon as he walked into the clinic building and noticed a ‘chemical smell’, that of isopropyl alcohol. He experienced the same nausea when returning for routine follow-up visits, even though he knew he would not receive treatment. The nausea gradually disappeared over repeated follow-up visits. Nesse et al. (1980) reported that about 44% of the patients being treated for lymphoma demonstrated such AN. AN is best understood as a classically conditioned response (CR) (Pavlov, 1927).
Control over AN could be exerted at the time of conditioning or at the time of re-exposure to the conditioned stimulus (CS). If an anti-emetic drug is presented at the time of conditioning, then a reduction in AN would be the result of an attenuated unconditioned response (UCR); that is, reduced nausea produced by the toxin at the time of conditioning thereby attenuating the establishment of the CR. Indeed, when administered during the chemotherapy session, the 5-HT3 antagonist, granisetron, has been reported to reduce the incidence of AN in repeat cycle chemotherapy treatment (Aapro et al., 1994). On the other hand, if a drug is delivered prior to re-exposure to cues previously paired with the toxin-induced nausea, then suppressed AN would be the result of attenuation of the expression of the CR (conditioned nausea); the 5-HT3 antagonists are ineffective at this stage (Nesse et al., 1980; Morrow and Dobkin, 1988; Reynolds et al., 1991; Stockhorst et al., 1993; Aapro et al., 1994; Ballatori and Roila, 2003; Hickok et al., 2003).
Anecdotal evidence suggests that Δ9-THC alleviates AN in chemotherapy patients (Grinspoon and Bakalar, 1993; Iversen, 2000). Although there has been considerable experimental investigation of unconditioned retching and vomiting in response to toxins, there have been relatively few reports of conditioned retching; that is, emetic reactions elicited by re-exposure to a toxin paired cue. Conditioned retching has been observed to occur in coyotes, wolves and hawks upon re-exposure to cues previously paired with lithium-induced toxicosis (Garcia et al., 1977) and ferrets have been reported to display conditional emetic reactions during exposure to a chamber previously paired with lithium-induced toxicosis (Davey and Biederman, 1998).
The S. murinus displays conditioned retching when returned to a chamber previously paired with a dose of lithium that produced vomiting (Parker and Kemp, 2001). Furthermore, this conditioned retching reaction is suppressed by pretreatment with Δ9-THC. This effect was replicated more recently and extended to demonstrate that CBD also interferes with the expression of conditioned retching in the shrew, but the 5-HT3 antagonist ondansetron was completely ineffective (Parker et al., 2006). The doses employed were selected on the basis of their potential to interfere with toxin-induced vomiting in the S. murinus(Kwiatkowska et al., 2004, Parker et al., 2004).
Rats also display conditioned gaping reactions when re-exposed to a context previously paired with LiCl-induced nausea (Limebeer et al., 2006; 2008; Rock et al., 2008). Following four pairings of a distinctive, vanilla odour-laced chamber with LiCl-induced illness, rats were returned to the context for 30 min and received a 1 min intraoral infusion of novel saccharin solution every 5 min. During the infusions, the rats displayed gaping reactions. Surprisingly, the rats also gaped during intervals when they were not being infused with saccharin while in the LiCl-paired context. It was further demonstrated that Δ9-THC, but not ondansetron, interfered with the conditioned gaping response during both infusion and inter-infusion intervals.
The finding that rats express conditioned gaping responses when re-exposed to an odour-laced context previously paired with LiCl during inter-infusion intervals (Limebeer et al., 2006) suggests that LiCl-paired cues in the absence of the flavour can elicit conditioned nausea. Meachum and Bernstein (1992) had previously shown the re-exposure to a lithium-paired odour cue elicited gaping reactions in rats. Recently, Limebeer et al. (2008) found that even in the absence of a flavoured solution or a distinctive odour, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium, as well as a low dose of lithium and provocative motion. Most recently, Rock et al. (2008)reported that CBD (within a limited dose range 1–5 mg·kg−1, but not 10 mg·kg−1) and the FAAH inhibitor, URB597, prevented the expression of conditioned gaping elicited by the lithium-paired context. The effect of URB597 was reversed by rimonabant, indicating a CB1 mechanism of action. Indeed, inhibition of FAAH by URB597 also prevented the establishment of LiCl-induced conditioned gaping elicited by the contextual cues when administered 2 h prior to each conditioning trial. These results suggest that cannabinoid compounds may be effective agents in the treatment of AN in chemotherapy patients.
Since the discovery of the mechanism of action of cannabinoids, our understanding of the role of the endocannabinoid system in the control of nausea and vomiting has greatly increased. In the ferret and shrew models, the site of action has been identified in the emetic area of the brainstem, the DVC. The shrew model, in particular, is cost effective for the evaluation of the anti-emetic properties of agents. The conditioned gaping response in the rat has provided a glimpse into the anti-nausea mechanisms of action of cannabinoids, in the absence of a vomiting response. Since nausea is a more difficult symptom to control than vomiting, the gaping model may serve as a useful tool for the development of new anti-nausea treatments, as well as for the evaluation of the potential side effects of nausea in newly developed pharmacological treatments. Recent work has also supported anecdotal reports that cannabis may attenuate AN. Using the S. murinus and the rat models of AN, both Δ9-THC and CBD effectively prevented conditioned retching and conditioned gaping (respectively) elicited by re-exposure to a lithium-paired chamber.
Although chemotherapy-induced vomiting is well controlled in most patients by conventionally available drugs, nausea (acute, delayed and anticipatory) continues to be a challenge. Nausea is often reported as more distressing than vomiting, because it is a continuous sensation (e.g. deBoer-Dennert et al., 1997; Andrews and Horn, 2006). Indeed, this distressing symptom of chemotherapy treatment (even when vomiting is pharmacologically controlled) can become so severe that as many as 20% of patients discontinue the treatment (Jordan et al., 2005). Both preclinical and human clinical (e.g. Abrahamov et al. 1995; Meiri et al., 2007) research suggests that cannabinoid compounds may have promise in treating nausea in chemotherapy patients.
Animal models of vomiting have been valuable in elucidating the neural mechanisms of the emetic reflex (e.g. Hornby, 2001); however, the neural mechanisms of nausea are still not well understood (Andrews and Horn, 2006). One limitation in the preclinical screening of the nauseating side effect of compounds and the potential of compounds to treat nausea has been the lack of a reliable preclinical rodent model of nausea. For years researchers have been using conditioned taste avoidance in rats as a model of nausea, but it has been well documented that non-nauseating treatments also produce taste avoidance – it is not a selective measure of nausea (e.g. Parker et al., 2008). However, the considerable amount of evidence reviewed above indicates that conditioned disgust in rats elicited by an illness-paired flavour (e.g. Parker et al., 2008) or an illness-paired context (e.g. Rock et al., 2008) represents a selective and sensitive rodent model of nausea. This model may be a useful tool for elucidating the neurobiology of nausea and the role that the endocannabinoid system plays in the regulation of this distressing condition.
This research was supported by a research grant to L.P. (92057) from the Natural Sciences and Engineering Research Council of Canada.
|5-HT3||5-hydroxytryptamine receptor 3|
|5-HT1A||5-hydroxytryptamine receptor 1A|
|CB1||cannabinoid receptor 1|
|CB2||cannabinoid receptor 2|
|DMNX||doral motor nucleus of the vagus|
|DRN||dorsal raphe nucleus|
|DVC||dorsal vagal complex|
|FAAH||fatty acid amide hydrolase|
|Gi||inhibitory G protein subunit|
|MRN||medial raphe nucleus|
|NTS||nucleus of the solitary tract|
|S||murinus, Suncus murinus|
|TRPV1||transient receptor potential vanilloid 1|
Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting.
- Fundació Institut Català de Farmacologia, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV.
Patients suffering from CINV despite prophylaxis with standard anti-emetic treatment were randomized to CBM or placebo, during the 120 h post-chemotherapy period, added to standard anti-emetic treatment. Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events (AEs). The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response.
Seven patients were randomized to CBM and nine to placebo. Only one patient in the CBM arm was withdrawn due to AEs. A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [5/7 (71.4%) with CMB vs. 2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], due to the delayed period. The incidence of AEs was higher in the CBM group (86% vs. 67%). No serious AEs were reported. The mean daily dose was 4.8 sprays in both groups.
Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial.
© 2010 Department of Health, Generalitat of Catalonia. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.
The role of cannabinoids in regulation of nausea and vomiting, and visceral pain.
- Section of Gastroenterology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
Marijuana derived from the plant Cannabis sativa has been used for the treatment of many gastrointestinal (GI) disorders, including anorexia, emesis, abdominal pain, diarrhea, and others. However, its psychotropic side effects have often limited its use. Several cannabinoid receptors, which include the cannabinoid receptor 1 (CB1), CB2, and possibly GPR55, have been identified throughout the GI tract. These receptors may play a role in the regulation of food intake, nausea and emesis, gastric secretion and gastroprotection, GI motility, ion transport, visceral sensation, intestinal inflammation, and cell proliferation in the gut. However, the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system has shed new knowledge in this field. Thus far, despite evidence of visceral sensitivity inhibition in animal models, data in irritable bowel syndrome (IBS) patients is scarce and not supportive. Furthermore, many compounds that either act directly at the receptor or increase (or reduce) ligand availability have the potential to affect other brain functions and cause side effects. Novel drug targets such as FAAH and monoacylglycerol lipase (MAGL) inhibitors appear to be promising in animal models, but more studies are necessary to prove their efficiency. The promise of emerging drugs that are more selective and peripherally acting suggest that, in the near future, cannabinoids will play a major role in managing an array of GI diseases.
Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system.
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1. Electronic address: firstname.lastname@example.org.
- Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.
- Department of Psychology, University of Guelph, Guelph, ON, Canada.
Nausea and vomiting (emesis) are important elements in defensive or protective responses that animals use to avoid ingestion or digestion of potentially harmful substances. However, these neurally-mediated responses are at times manifested as symptoms of disease and they are frequently observed as side-effects of a variety of medications, notably those used to treat cancer. Cannabis has long been known to limit or prevent nausea and vomiting from a variety of causes. This has led to extensive investigations that have revealed an important role for cannabinoids and their receptors in the regulation of nausea and emesis. With the discovery of the endocannabinoid system, novel ways to regulate both nausea and vomiting have been discovered that involve the production of endogenous cannabinoids acting centrally. Here we review recent progress in understanding the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system, and we discuss the potential to utilize the endocannabinoid system in the treatment of these frequently debilitating conditions.
Brainstem; CB(1) receptor; CB(2) receptor; Cannabis; Emesis; Insular cortex; Serotonin
Regulation of nausea and vomiting by cannabinoids.
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Ontario, N1G 2W1, Canada. DA-9789
Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB(1) agonism suppresses vomiting, which is reversed by CB(1) antagonism, and CB(1) inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ(9) -THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB(1) receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT(1A) receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.
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